Program Director/Principal Investigator (Last, First, Middle): El-Sadr, Wafaa M. Project Summary The HIV epidemic continues to rage uncontained in many countries around the world, particularly in sub Saharan Africa. Lesotho, a small country in Southern Africa, has been severely affected with an estimated HIV seroprevalence of 23% among adults, the third highest rate in the world. Discordant couples for HIV where one partner is HIV infected and the other HIV negative represent a situation where the HIV negative partner is at high risk for acquiring HIV. Such transmission within married or cohabitating couples has been recognized as a major contributor to the spread of HIV. Thus, effective interventions that aim at prevention of transmission within HIV sero-discordant heterosexual couples are likely to have an important public health impact. We propose an innovative clinical trial, the Enhanced Prevention in Couples Study (EPIC Study), that aims at evaluating the effect of Enhanced Prevention Package (EPP) versus Standard of Care (SOC) on risk of HIV acquisition in HIV negative partners within HIV discordant couples enrolled from antenatal clinics (ANCs) in Lesotho. The Enhanced Prevention Package will include the following interventions: 1) antiretroviral therapy (ART) for the HIV infected partners at threshold of <500 CD4 cell count, 2) couple-focused counseling for decreasing sexual risk behavior and enhancing adherence with ART, and 3) circumcision for HIV negative male partners. The goals of this application are as follows: A. To describe the design of the EPIC study which will assess an Enhanced Prevention Package inclusive of biomedical and behavioral interventions through a randomized controlled trial. B. To conduct feasibility and acceptability studies of key components of the Enhanced Prevention Package in the form of three focused studies: 1) assessment of strategies for recruitment and HIV testing of male partners of women participating in ANCs, 2) determination of feasibility of couple-focused counseling for sexual risk reduction and ART adherence and 3) evaluation of acceptability of male circumcision. C. To model the potential effect of the Enhanced Prevention Package in terms of its effect on HIV transmission in Lesotho. D. To utilize the findings from the three studies, the results of the modeling and information garnered from the literature and from programs in Lesotho in refining the design of EPIC study The team of investigators involved in this application includes a diversity of expertise and a wealth of experience. They include epidemiologists, behavioral scientists, clinical researchers, program implementers as well as modeling and statistical experts. They are partnering with collaborators in Lesotho in the planning of this research. They have extensive experience in establishing programs in sub Saharan Africa and have successfully designed and implemented prevention studies in diverse settings.